Abstract
Accumulation of misfolded proteins challenges cellular proteostasis and is implicated in aging and chronic disorders. Cancer cells, moreover, face an elevated level of basal proteotoxic stress; hence, exacerbating endoplasmic reticulum (ER) stress has been shown to induce programmed cell death while enhancing anticancer immunogenicity. We hypothesize that hydrophobic abiotic macromolecules can trigger a similar stress response. Most polymers and nanoparticles, however, are sequestered in endo/lysosomes after endocytosis, which prevents their interaction with the proteostasis machinery. We adopted an in situ polymerization approach to synthesize polymers in cells with cell-permeable monomers. Specifically, we developed a biocompatible polycondensation between l-cysteine and 2-cyanobenzothiazole (CBT) with photochemical control to form insoluble poly(luciferin) aggregates. We identified that in situ polymerization activates the BiP-PERK-CHOP pathway of the unfolded protein response and that the unresolved ER stress initiates a form of regulated cell death consistent with paraptosis. In addition, the dying cells emit damage-associated molecular patterns (DAMPs), indicating an immunogenic cell death that could potentiate antitumor immunity. Our results show that in situ polymerization mimics misfolded protein aggregates to induce proteotoxic stress and cancer cell death, offering a novel therapeutic strategy to exploit cancer vulnerability.